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PubMed1997

Prostaglandins induce proliferation of rat hepatocytes through a prostaglandin E2 receptor EP3 subtype.

We characterized the proliferative action of prostaglandins (PGs) in relation to their membrane receptors on rat hepatocytes in primary culture. PGs in the order 16,16-dimethyl PGE2 > PGE2 > PGF2alpha >> PGD2 augmented epidermal growth factor (EGF)/insulin-induced DNA synthesis, assessed by [(3)H]thymidine incorporation, in a concentration-dependent manner, whereas PGs alone did not stimulate basal DNA synthesis without EGF and insulin. The cells exhibited [(3)H]PGE2 binding sites that were displaced by unlabeled PGs in the order PGE1 = PGE2 > PGF2alpha > PGD2. PGE2 inhibited glucagon-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation concentration dependently. The mean effective concentration for DNA synthesis, median inhibitory concentration for cAMP accumulation, and dissociation constant for [(3)H]PGE2 binding at 25 degrees C were almost identical (approximately 70 nM). Treatment of the cells with pertussis toxin (100 ng/ml), which ADP-ribosylated most of the 41-kDa substrate, abolished the proliferative effects of PGs. We detected the expression of mRNA of the EP3 subtype PGE2 receptor using reverse transcription-polymerase chain reaction. Moreover, an EP3 agonist, enprostil, but not the EP1 agonist 17-phenyl-trinor-PGE2 or the EP2/EP4 agonist 11-deoxy-PGE1, stimulated EGF/insulin-induced DNA synthesis. These results indicate that PGs act as comitogenic growth factors through the EP3 subtype PGE2 receptor coupled with G(i) protein in cultured rat hepatocytes.

Animals↗

PubMed2004

Pharmacological characterization and identification of EP3 prostanoid receptor binding sites in hamster uterus homogenates.

The pharmacological properties of [(3)H]-prostaglandin E(2) ([(3)H]-PGE(2)) binding to washed homogenates of hamster uterus were determined. Scatchard analysis of competition data yielded dissociation constants (K(d)s) of 30.9 +/- 5.6 nM (n = 3) and apparent receptor density (B(max)) of 25.25 +/- 1.89 pmol g(-1) wet weight tissue (74 +/- 8% specific binding). Competition studies yielded the following affinity parameters (K(i)) for various prostanoids: GR63799X = 13 4 nM; PGE(2) = 17 +/- 3 nM; sulprostone = 64 +/- 5 nM; enprostil = 67 +/- 3 nM; misoprostol = 124 +/- 15 nM; cloprostenol = 187 +/- 33 nM; carba-prostacyclin = 260 +/- 167 nM; iloprost = 555 +/- 162 nM; PGF(2 alpha) = 767 +/- 73 nM; PGD(2) > 3560 nM; fluprostenol = 11 790 +/- 2776 nM; RS93520 = 21 558 +/- 14 228 nM. These data closely matched the pharmacological profile of previously described EP(3) receptors such as in bovine corpus luteum (BCLM) and the cloned mammalian EP(3) receptors. The high correlation between the current hamster uterus pharmacology data vs the EP(3) receptor binding in BCLM (r = 0.94; P < 0.0001), vs cloned human EP(3) receptor (r = 0.94, P < 0.0001), vs the cloned mouse EP(3) receptor binding (r = 0.78; P < 0.002), vs cloned rat EP(3) receptor (r = 0.9, P < 0.0004), and vs EP(3) receptor-mediated functional responses (r = 0.72, P < 0.02) substantiated the conclusion that the hamster uterus contains EP(3) receptor binding sites.

Animals↗

PubMed1989

Side effects of anti-ulcer prostaglandins: an overview of the worldwide clinical experience.

Anti-ulcer prostaglandins (PG)--misoprostol, enprostil and rioprostil--have been given to more than 5000 patients in short-term studies on gastric and duodenal ulcer. Analysis of these studies shows the drugs to be safe. Their side effects appear to be dose-dependent and mainly restricted to the gastrointestinal system, the major syndromes being diarrhoea and abdominal pain. The clinical relevance of PG-related unwanted effects, though in average exceeding that of H2-blockers, seems to be sufficiently low. In terms of safety efficacy, however, they appear inferior to H2-antagonists, so their routine use in preference to the latter compounds is still premature.

Alprostadil↗

PubMed1987

Pharmacological management of patients with peptic ulcer disease: prospects for the late 1980's.

Over the past ten years there have been major advances in the physician's ability to treat patients with peptic ulcer disease. Cimetidine continues to be the standard against which newer therapies are generally compared, although ranitidine is equally effective for short-term therapy, more effective for maintenance therapy, and has a superior safety profile. Famotidine is an even more potent H2 receptor antagonist, and initial clinical studies are promising. The initial concern for the development of gastric carcinoid lesions in rodents, maintained for long periods on high doses of omeprazole, defused the initial enthusiasm for this hydrogen-potassium ATPase "proton pump" inhibitor, but recent studies continue to show a marked efficacy of this agent for the short-term care of patients with gastric or duodenal ulcers and for the management of patients with the Zollinger-Ellison syndrome. Sulcrate continues to enjoy wide popularity for acute and chronic care of acid peptic disorders because of its local action and minimal adverse effects. Pirenzepine is effective in achieving and maintaining healing, but prevalence of anticholinergic side-effects has hampered enthusiasm for its widespread use. The 2 forerunners in the prostaglandin analogues arena, misoprostol and enprostil, are antisecretory agents when given in sufficiently high doses. These orally administered prostaglandins have a favourable safety profile, and their only adverse effect is that of the development of transient mild diarrhea. Finally, while antacids continue to be used in large amounts because of their over-the-counter availability, their clinical usefulness is limited by their unpalatable taste and the relatively large amounts usually required to achieve ulcer healing.

Alprostadil↗

PubMed1990

Evaluation of putative cytoprotective properties of antiulcer drugs using quantitative histological techniques.

The capacity for cytoprotection has been claimed for a number of drugs that may have a place in the treatment of peptic ulcer disease. In this study we have used quantitative histological criteria to evaluate the ability of these drugs to be cytoprotective and have compared their effects with that of natural prostaglandin E2 (PG). The standard rat model, with injury by instillation of 1 ml of absolute ethanol, has been used. Putative cytoprotective agents were administered 15 min prior to ethanol. Each animal was sacrificed 15 min after ethanol exposure. The stomach was removed and studied using an established quantitative histological technique. This technique provides a measure of the surface area of mucosa damaged and of the volume of mucosa damaged. Ethanol alone caused damage to 76% of the area of the rat stomach and 14% of the volume of the rat gastric mucosa. Pretreatment by PG (25 micrograms/ml) resulted in reduction of the area of damage to 45% and reduction of the percentage volume damage to 2.2%. The synthetic analog of PGE2, Enprostil (1 microgram/ml) achieved similar protective effects. With pretreatment with colloidal bismuth subcitrate (10 mg/kg) or sucralfate (25 mg/kg), no protection against the surface area damaged by ethanol was seen, but there was a marked reduction of the volume of mucosa damaged. Indomethacin pretreatment augmented the damage caused by ethanol. The protective effects of colloidal bismuth subcitrate and sucralfate were not blocked by pretreatment with indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1997

Molecular cloning and characterization of the four rat prostaglandin E2 prostanoid receptor subtypes.

We have characterized the rat prostanoid EP1, EP2, EP3alpha and EP4 receptor subtypes cloned from spleen, hepatocyte and/or kidney cDNA libraries. Comparison of the deduced amino acid sequences of the rat EP receptors with their respective homologues from mouse and human showed 91% to 98% and 82% to 89% identity, respectively. Radioreceptor binding assays and functional assays were performed on EP receptor expressing human embryonic kidney (HEK) 293 cells. The KD values obtained with prostaglandin E2 for the prostanoid receptor subtypes EP1, EP2, EP3alpha and EP4 were approximately 24, 5, 1 and 1 nM, respectively. The rank order of affinities for various prostanoids at the prostanoid receptor subtypes EP2, EP3alpha and EP4 receptor subtypes was prostaglandin E2 = prostaglandin E1 > iloprost > prostaglandin F2alpha > prostaglandin D2 > U46619. The rank order at the prostanoid EP1 receptor was essentially the same except that iloprost had the highest affinity of the prostanoids tested. Of the selective ligands, butaprost was selective for prostanoid EP2, M&B28767 and sulprostone were selective for EP3alpha and enprostil displayed dual selectivity, interacting with both prostanoid receptor subtypes EP1 and EP3alpha. All four receptors coupled to their predominant signal transduction pathways in HEK 293 cells. Notably, using a novel aequorin luminescence assay to monitor prostanoid EP1 mediated increases in intracellular calcium, both iloprost and sulprostone were identified as partial agonists. Finally, by Northern blot analysis EP3 transcripts were most abundant in liver and kidney whereas prostanoid EP2 receptor mRNA was expressed in spleen, lung and testis and prostanoid EP1 receptor mRNA transcripts were predominantly expressed in the kidney. The rat prostanoid EP1 probes also detected additional and abundant transcripts present in all the tissues examined. These were found to be related to the expression of a novel protein kinase gene and not the prostanoid EP1 gene [Batshake, B., Sundelin, J., 1996. The mouse genes for the EP1 prostanoid receptor and the novel protein kinase overlap. Biochem. Biophys. Res. Commun. 227. 1329-1333].

Aequorin↗

PubMed1999

Prostaglandin DP receptors positively coupled to adenylyl cyclase in embryonic bovine tracheal (EBTr) cells: pharmacological characterization using agonists and antagonists.

Various prostaglandin agonists representing various classes of receptor subtypes were evaluated for their ability to stimulate adenylyl cyclase via the endogenous DP receptor in embryonic bovine tracheal (EBTr) cells. Two antagonists were used to block the agonist-induced cyclic AMP production. ZK118182 (EC50 = 16+/-4 nM), RS-93520 (EC50 = 23+/- 4 nM), SQ27986 (EC50 = 33+/-9 nM), ZK110841 (EC50 = 33+/-5 nM), BW245C (EC50 = 59+/-19 nM) and PGD2 (EC50=101+/-10 nM) (n = 4-70) were the most potent agonists. Whilst most compounds were full agonists (Emax = 100% relative to PGD2), BW245C was significantly more efficacious than PGD2 (Emax = 121+/-3%; P<0.001) and RS-93520 appeared to be a partial agonist (Emax = 64+/-9%; P<0.001). Agonists from the EP (e.g. enprostil; misoprostol; butaprost), FP (e.g. cloprostenol; fluprostenol; PHXA85), IP (iloprost; PGI2) and TP (U46619) prostanoid receptor classes were weak agonists or inactive in the EBTr cell assay system. The DP-receptor antagonist, BWA868C, showed a competitive antagonist profile with pA2 values of 8.00+/-0.02 and 8.14+/-0.13 in Schild analyses with two structurally different agonists, BW245C and ZK118182, respectively (n = 3). AH6809, another purported DP-receptor antagonist, weakly inhibited PGD2- and ZK 18182-induced cyclic AMP production (K(i)s = 808+/-193 nM and 782+/-178 nM, respectively). The current studies have characterized the DP receptor positively coupled to adenylyl cyclase in EBTr cells using a wide range of agonist and antagonist prostaglandins. These data support the utility of the EBTr cell line as a useful tool for the evaluation of DP receptor agonists and antagonists and for profiling other classes of prostaglandins.

Adenosine Monophosphate↗

PubMed2000

Pharmacological characterization of [(3)H]-prostaglandin E(2) binding to the cloned human EP(4) prostanoid receptor.

Prostaglandin (PG) E(2) (PGE(2)) is a potent prostanoid derived from arachidonic which can interact with EP(1), EP(2), EP(3) and EP(4) prostanoid receptor subtypes. Recombinant human EP(4) receptors expressed in human embryonic kidney (HEK-293) cells were evaluated for their binding characteristics using [(3)H]-PGE(2) and a broad panel of natural and synthetic prostanoids in order to define their pharmacological properties. [(3)H]-PGE(2) binding was optimal in 2-[N-Morpholino]ethanesulphonic acid (MES) buffer (pH 6.0) yielding 98+/-0.7% specific binding. The receptor displayed high affinity (K(d)=0.72+/-0.12 nM; n=3) for [(3)H]-PGE(2) and interacted with a saturable number of binding sites (B(max)=6.21+/-0.84 pmol mg(-1) protein). In competition studies, PGE(2) (K(i)=0.75+/-0.03 nM; n=12) and PGE(1) (K(i)=1.45+/-0.24 nM; n=3) displayed high affinities, as did two derivatives of PGE(1), namely 11-deoxy-PGE(1) (K(i)=1.36+/-0.34 nM) and 13,14-dihydro-PGE(1) (K(i)=3.07+/-0.29 nM). Interestingly, synthetic DP receptor-specific agonists such as BW245C (K(i)=64.7+/-1.0 nM; n=3) and ZK118182 (K(i)=425+/-42 nM; n=4), and the purported EP(3) receptor-specific ligand enprostil (K(i)=43.1+/-4.4 nM), also displayed high affinity for the EP(4) receptor. Two known EP(4) receptor antagonists were weak inhibitors of [(3)H]-PGE(2) binding akin to their known functional potencies, thus: AH23848 (K(i)=2690+/-232 nM); AH22921 (K(i)=31,800+/-4090 nM). These studies have provided a detailed pharmacological characterization of the recombinant human EP(4) receptor expressed in HEK-293 cells.

Binding, Competitive↗

PubMed1997

Glucagon-like peptide 1 (GLP-1) as a new therapeutic approach for type 2-diabetes.

Glucagon-like peptide 1 (GLP-1) is a physiological incretin hormone in normal humans explaining in part the augmented insulin response after oral versus intravenous glucose administration. In addition, GLP-1 also lowers glucagon concentrations, slows gastric emptying, stimulates (pro)insulin biosynthesis, reduces food intake upon intracerebroventricular administration in animals, and may, in addition, enhance insulin sensitivity. Therefore, GLP-1, in many aspects, opposes the Type 2-diabetic phenotype characterized by disturbed glucose-induced insulin secretory capacity, hyperglucagonaemia, moderate insulin deficiency, accelerated gastric emptying, overeating (obesity) and insulin resistance. The other incretin hormone, gastric inhibitory polypeptide (GIP), has lost almost all its activity in Type 2-diabetic patients. In contrast, GLP-1 glucose-dependently stimulates insulin secretion in diet- and sulfonylurea-treated Type 2-diabetic patients and also in patients under insulin therapy long after sulfonylurea secondary failure. Exogenous administration of GLP-1 ([7-37] or [7-36 amide]) in doses elevating plasma concentrations to approximately 3-4 fold physiological postprandial levels fully normalizes fasting hyperglycaemia in Type 2-diabetic patients. The half life of GLP-1 is too short to maintain therapeutic plasma levels for sufficient periods by subcutaneous injections. Current research activities aim at finding GLP-1 analogues with more suitable pharmacokinetic properties than the original peptide. Another approach could be the augmentation of endogenous release of GLP-1, which is abundant in L cells of the lower small intestine and the colon. Interference with sucrose digestion using alpha-glucosidase inhibition moves nutrients into distal parts of the gastrointestinal tract and, thereby, prolongs and augments GLP-1 release. Enprostil, a prostaglandin E2 analogue, fully suppresses GIP responses, while only marginally affecting insulin secretion and glucose tolerance after oral glucose, suggesting compensatory hypersecretion of additional insulinotropic peptides, possibly including GLP-1. Given the large amount of GLP-1 present in L cells, it appears worthwhile to look for more agents that could 'mobilize' this endogenous pool of the 'antidiabetogenic' gut hormone GLP-1.

Blood Glucose↗

PubMed1987

Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretory drugs.

FVMany different dosage schedules of antisecretory drugs for the treatment of duodenal ulcer are recommended. The relationship between degree of acid suppression and therapeutic efficacy has not been precisely defined for these drugs. We have examined the association between suppression of intragastric acidity and duodenal ulcer healing rates for a number of therapeutic regimens. For the H2 receptor antagonists alone, the most significant correlation with healing rates was with suppression of intragastric acidity at night (r = 0.926; p = 0.0001). When other classes of drug: high dose antacid, omeprazole and a synthetic prostaglandin (enprostil) were included in the analysis, the closest correlation was with suppression of total 24 hour intragastric acidity (r = 0.911; p less than F0.0001). Stepwise linear regression analysis was used to investigate the relative contributions to healing of suppression of acidity during the day and night. Suppression of nocturnal acidity was found to be the single most important factor in explaining healing rates. No further benefit was obtained with daytime suppression for H2 receptor antagonists; suppression of acidity at night accounted for 86.1% of the observed variation in healing rates among different regimens of H2 receptor antagonists. When all classes of drugs were analysed, inclusion of daytime suppression produced a significant improvement in correlation over nocturnal suppression alone. Drug regimens providing potent suppression of nocturnal acidity produce the highest healing rates in controlled clinical trials. The healing rate for any dose regimen of an antisecretory drug can be predicted from a knowledge of its effect on intragastric acidity. For the H2 receptor antagonists, suppression of nocturnal acidity is the most relevant in this context. Moderate suppression of acidity achieves ulcer healing rates at four to eight weeks which are comparable with those seen with potent suppression at two to four weeks. Increasing degrees of suppression merely accelerate healing.

Anti-Ulcer Agents↗

PubMed1997

EP1 receptor blockade attenuates both spontaneous tone and PGE2-elicited contraction in guinea pig trachealis.

We assessed the effect of prostaglandin (PG) E2 on tone of guinea pig tracheal smooth muscle (TSM) strips in vitro. In the presence of spontaneous tone [ST; i.e., no indomethacin (-Indo)], exogenous PGE2 caused a significant relaxation of ST at concentrations > 10(-6) M [to -127 +/- 40.8% electric field stimulation (EFS); P = 0.001 vs. baseline ST] and at concentrations < 10(-6) M caused a variable change in contractile force (51.6 +/- 29.6% EFS; P = NS vs. baseline ST). In the absence of ST (i.e., +Indo) 10(-10) to 10(-7) M PGE2 elicited contraction of TSM to 126.3 +/- 10.5% EFS (P = 0.001 vs. baseline) and no relaxation. Addition of prostanoid EP1 receptor antagonist (either AH-6809 or SC-19220) to Indo-treated TSM caused a substantial rightward shift and attenuation of contraction in response to PGE2 (55.9 +/- 16.8% EFS for 10(-5) MAH-6809; P = 0.007 vs. +Indo alone, and 80.5 +/- 12.7% EFS for 10(-5) M SC-19220, P = 0.03 vs. +Indo alone). We further assessed the effect of EP1 and EP4 receptor antagonism on the ST of guinea pig TSM strips. Concentration-response curves to the EP1 receptor-specific antagonists AH-6809 or SC-19220 and the EP4 receptor-specific antagonist AH-23848B were generated (10(-7) to 10(-5) M); AH-6809 caused relaxation of ST to 11.4 +/- 2.9% ST (P = 0.001 vs. initial ST) and SC-19220 caused relaxation to 31.0 +/- 12.7% ST (P = 0.02 vs. initial ST). However, AH-23848B did not significantly affect ST (to 60.9 +/- 7.7% ST; P = 0.07 vs. initial ST). Furthermore, AH-6809 specifically inhibited contraction elicited by the EP1 receptor agonist Iloprost but had no effect on contraction elicited by the EP3 receptor agonist Enprostil. We demonstrate that in the presence of ST (-Indo), exogenous PGE2 elicits a biphasic response in guinea pig TSM in which relaxation predominates. In the absence of ST (+Indo), exogenous PGE2 elicits contraction of guinea pig TSM strips that is inhibited by EP1 receptor-specific antagonism. Spontaneous tone of guinea pig TSM strips also is inhibited by EP1 receptor antagonism. Our data suggest that both PGE2-elicited contraction and ST of guinea pig TSM are mediated through activation of EP1 prostanoid receptors.

Acetylcholine↗

PubMed1990

Radiation and the small intestine. Future perspectives for preventive therapy.

Radiotherapy continues to enjoy a prominent role in the treatment of certain human tumors. Unfortunately, the undesired effect of radiation upon normal intestinal tissue often limits its therapeutic potential. While there is abundant information on the effects of radiation on the morphology of the intestine and on the proliferative process which occurs in the intestinal crypts, there is a paucity of information on the early and late effects of sublethal doses of radiation upon the absorptive functions of the intestine. The intestinal epithelium has a rapid turnover rate and is highly radiosensitive. Radiotherapy for malignant human neoplasms is a relatively safe and effective form of treatment, but it may become limited by its undesired side effects upon the gastrointestinal tract. A variety of clinical tests have been suggested as potential indicators of impending intestinal damage, but there is little information on the time course of radiation damage and the associated impairment of intestinal function. Such basic information is essential to assess early functional changes and to thereby allow for the development of suitable clinical tests to allow for the prediction of impending intestinal damage. Provision of this information to the radiotherapist would permit alterations to the timing or dose schedules of radiotherapy and would allow continued treatment, while avoiding or reducing unwanted side effects. In recent years, there has been extensive research on radiation injury to small intestine. This article will review some of the progress in this field, and will focus on potential future therapy to prevent or treat radiation damage to the intestine. These agents include WR-2721, enprostil, vasopressin, defined-formula diets and alterations in the ratio of dietary polyunsaturated-saturated fatty acids.

Forecasting↗

PubMed2002

Cloned human EP1 prostanoid receptor pharmacology characterized using radioligand binding techniques.

Prostaglandins such as prostaglandin E2 (PGE2) interact with EP-class prostanoid receptors including EP1, EP2, EP3 and EP4 subtypes. We have conducted a detailed pharmacological characterization of the binding of [3H]-PGE2 to recombinant human EP1 prostanoid receptors expressed in human embryonic kidney (HEK-293) cells using a broad panel of natural and synthetic prostanoids. The receptor displayed high affinity (Kd = 16.0 +/- 0.69 nM; n = 3) for [3H]-PGE2, and was expressed at high levels (Bmax =3.69 +/- 0.30 pmol (mg protein)(-1)) in cell membranes of HEK-293 cells. Specific binding constituted 97.5 +/- 1.4% (n = 12) of the total binding. In competition assays, the rank order of affinities of natural prostanoids for the receptor was PGE2 > PGE1 > PGF2 > PGI2 > PGD2. PGE2 was more effective than PGE1 at displacing bound [3H]-PGE2 (Ki for PGE2 = 14.9 +/- 2.2 nM; Ki for PGE1 = 165 +/- 29 nM). The affinities of enprostil (Ki = 14.5 +/- 3.1 nM) and 17-phenyl-omega-trinor-PGE2 (Ki = 7.3 +/- 2.7 nM) for the receptor were quite similar to that of PGE2, while that of sulprostone (Ki = 137 + 13 nM) more closely resembled PGE1. Some compounds historically classified as specific for DP prostanoid receptors bound with relatively high affinity to the recombinant human EP1 receptor (e.g. ZK118182 (K = 73.4 +/- 8.6 nM) and ZK110841 (K = 166 +/- 20 nM)). All FP (e.g. travoprost acid, fluprostenol), IP (iloprost) and TP (SQ29548) receptor-specific ligands exhibited low affinity (Ki > or = 1 microM).

Algorithms↗

PubMed1997

[A new model of delayed healing of acetic acid ulcers in rats by indomethacin via osmotic pump].

Gastric ulcers were produced in male Donryu rats (8-weeks-old) by subserosal injection of 20 microliters of 20% acetic acid. Five days later, an indomethacin (IND)-filled osmotic pump (OP) was implanted into the dorsal subcutaneous space in the rats and maintained for 2, 3 or 4 weeks. The natural healing of the acetic acid-induced ulcers was significantly (P < 0.05) delayed by administration of IND via OP implanted for 4 weeks. Two, 3 and 4 weeks after OP implantation, the plasma IND levels was 1.87 +/- 0.13, 2.43 +/- 0.16 and 0.74 +/- 0.26 (micrograms/ml), respectively, showing that a steady state IND plasma level was maintained for 3 weeks. The gastric mucosal PGE2 levels in rats with ulcers for 3 weeks after implantation of OP were significantly (P < 0.05) reduced by IND (IND(-):576.6 +/- 83.9 pg/mg, IND(+):355.6 +/- 34.7 pg/mg). Repeated administration of enprostil, famotidine and rabeprazole at 25 micrograms/kg, 100 mg/kg and 10 mg/kg (p.o., b.i.d.), respectively, showed anti-ulcer activity. Teprenone and rebamipide had only slight anti-ulcer activity. These findings indicated that this model of delayed healing of acetic acid ulcers by IND using OP is useful for investigating the anti-ulcer activity of drugs.

Acetates↗

PubMed1988

The significance of gastrin in the pathogenesis and therapy of peptic ulcer disease.

Gastrin, a polypeptide hormone secreted by G (gastrin)-cells in the antroduodenal mucosa, is not only a potent stimulant of gastric acid secretion but also exerts trophic actions on the parietal, chief and enterochromaffin-like cells in the oxyntic mucosa. Gastrin plays a crucial role in the pathogenesis of hypergastrinaemic peptic ulcer disease, i.e. in the Zollinger-Ellison syndrome, antral G-cell hyperfunction and retained excluded antrum after subtotal gastrectomy. In patients with normogastrinaemic duodenal ulcer disease the feedback mechanism between gastric acid and gastrin secretion is impaired, while in gastric ulcer patients gastrin secretion is appropriately regulated by gastric acid. Antisecretory drugs may exert varying effects on gastrin secretion. Potent antisecretory drugs, such as omeprazole, increase serum and antral gastrin concentrations, whereas histamine H2-receptor antagonists, such as cimetidine, ranitidine, famotidine and roxatidine, have little influence on gastrin. Interestingly, antisecretory doses of prostaglandin E2-analogues, such as enprostil and arbaprostil [15(R)-15-methylprostaglandin E2], inhibit gastrin secretion, while gastrin is not influenced by prostaglandin E1-analogues, e.g. misoprostol. Somatostatin and the somatostatin-analogue SMS 201-995 reduce serum gastrin levels and gastric acid secretion.

Anti-Ulcer Agents↗

PubMed1987

Prostaglandins in clinical treatment of gastroduodenal mucosal lesions: a review.

E-type prostaglandins inhibit gastric acid secretion and stimulate gastroduodenal bicarbonate and mucus secretion as well as the formation of hydrophobic surfactant-like phospholipids in the gastric epithelial cells. Furthermore, E-type prostaglandins have trophic effects on the gastro-duodenal mucosa. These effects may partly explain the unique protective effects of E-type prostaglandins against experimental damage of gastroduodenal mucosal lesions in animals and humans. E-type prostaglandins have been used in clinical trials on peptic ulcers, on upper gastrointestinal bleeding, and on mucosal lesions induced by non-steroid anti-inflammatory drugs. In nearly all trials natural prostaglandin E2 as well as the synthetic prostaglandin analogues arbaprostil, misoprostol, enprostil, rioprostil, trimoprostil, and rosaprostol accelerated the healing of peptic ulcers compared with placebo. The PGE analogues must be given in gastric acid antisecretory dosage to reach healing rates similar to those of cimetidine. The drugs seem to be safe, and diarrhoea--the main adverse effect--occurs rarely. Future studies are necessary to identify the place of prostaglandins among other drugs used in peptic ulcer treatment. In the treatment of acute upper gastrointestinal bleeding, arbaprostil was not more effective than placebo in spite of several case reports suggesting that prostaglandin E analogues would be helpful in these situations. E-type prostaglandins were effective in preventing gastroduodenal mucosal lesions caused by non-steroid anti-inflammatory drugs, but the long-term efficacy of prostaglandins has to be established in studies on patients under continuous anti-inflammatory treatment.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1989

Campylobacter pylori: Swedish experiences.

All patients referred for gastroscopy were investigated by Campylobacter pylori culture and antibody titration. An enzyme immunoassay was developed and found to have a negative predictive value of 0.997, which indicates that serologic tests could be used for screening of patients before gastroscopy. A close correlation was found between active and inactive duodenal and gastric ulcer and positive C. pylori culture. Small open treatment trials with the antibiotics doxycycline, tinidazole, amoxycillin, and norfloxacin were ineffective for the eradication of C. pylori. Treatment with the new anti-ulcer agents enprostil, rioprostil, and omeprazole had no effect on the presence of C. pylori.

Adult↗

PubMed1991

Effect of the prostaglandin E1 analogue misoprostol on the carbon tetrachloride-induced injury of rat liver cells in culture.

Previous investigators have reported a protective effect of some prostaglandins and of the prostaglandin E2 analogue enprostil on carbon tetrachloride (CCl4)-induced injury of liver cells. In the present study liver cells were isolated from the rat liver by collagenase perfusion and suspended in F-10 medium, containing 20% foetal bovine serum, 1% gentamicin, and 1% glutamine. In the first study cells were cultured in T-flasks with 3 ml suspension of 6 x 10(6) cells/ml, and in the second study (extended dose response) cells were cultured in tissue culture wells with 0.5 ml cell suspension. Misoprostol was added to groups of cultures 15 min before CCl4, 2 microliters/ml, and the number of living cells was counted 45 min after the first addition. The number of living cells was compared with those of other groups with CCl4 only and control groups. In the first experiment misoprostol was given in doses of 200, 400, and 800 ng/ml medium and in the second experiment in 0.1, 1, 10, 100, and 1000 ng/ml medium. CCl4 is an agent well known to be toxic to liver cells, and in cultures to which only CCl4 was added, the number of living cells was significantly reduced compared with controls. When 0.1 ng misoprostol was added before CCl4, no significant difference in the number of living cells was shown compared with cultures with CCl4 only. On the other hand, misoprostol given in doses from 1 ng to 1000 ng before CCl4 resulted in a higher number of living cells, indicating a protective effect.

Animals↗